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About one third of HIV patients suffer from HIV-associated distal sensory polyneuropathy (HIV-DSP), for which there is currently no FDA approved treatment. HIV viral proteins (HIV-1 envelope glycoprotein gp120 and trans-activator of transcription Tat) are known to be associated with mitochondrial dysfunction and neurotoxicity in the brain, but the pathogenic roles of the proteins in peripheral nerves are still unclear. To study if gp120 and/or Tat plays a role in HIV-DSP, indices of peripheral neuropathy were measured in gp120 transgenic (tg) mice, gp120 tg mice treated with Tenofovir disproxil fumarate (TDF, antiretroviral drug), Tat eye drop treated mice and doxycycline-inducible Tat tg mice. Pirenzepine (PZ), a selective muscarinic subtype-1 receptor (M1R) antagonist that reduces cholinergic constraint of mitochondrial function in sensory neurons and enhances nerve growth, was investigated as a potential therapeutic for HIV-DSP in these mouse models of HIV. Eight-month-old gp120 tg mice developed MNCV slowing which was exaggerated by concurrent TDF therapy. Interestingly, TDF also induced both MNCV slowing and thermal hyperalgesia in wild type (WT) mice suggesting novel neurotoxicity of this antiretroviral. Efficacy of PZ against indices of neuropathy in gp120 tg mice was inconclusive. Tat protein delivered by eye drops did not induce neuropathy in WT mice, whereas Tat tg mice developed MNCV slowing, thermal hypoalgesia and corneal nerve loss. These indices of neuropathy were prevented by PZ, which also induced tactile allodynia in WT mice when given by eye drop concurrent with Tat. My data suggested that gp120, TDF and Tat may all contribute to HIV-DSP, and that M1R antagonists may be a viable therapy against HIV-DSP but also have the potential to cause allodynia as a side effect.